T lymphocytes (i.e., T cells) play a key role in regulating immune responses in animals. Activation of T cells requires two signals delivered by antigen presenting cells to non-activated T cells. The first, or primary, signal is mediated by the interaction of the T cell receptor/CD3 complex (TcR/CD3) with MHC-associated antigenic peptide. The second, or costimulatory, signal regulates the T cell proliferative response and induction of effector functions. Costimulatory signals determine whether a T cell will be activated or inactivated to a state of tolerance. Molecules present on the surface of antigen presenting cells which are involved in T cell costimulation include B7 molecules. As known in the art, B7 molecules include two forms, B7-1 and B7-2, also known as CD80 and CD86, respectively. These molecules are counter-receptors for two ligands, CD28 and CTLA4. Both B7-1 and B7-2 bind both CD28 and CTLA4. Upon binding to CD28 or CTLA4, mouse B7 can cause T cells to proliferate and secrete interleukin-2 in conjunction with engagement of T cell receptor with a major histocompatability molecule complexed with peptide.
A full-length B7 protein is composed of several regions including, from the N-terminus, a signal peptide, an extracellular region, a transmembrane region, and a cytoplasmic region. The predicted amino acid sequence of B7-1 shares homology with members of the immunoglobulin (Ig) superfamily due to the presence of two contiguous Ig-like domains in the extracellular region. For example, in the mature mouse B7-1 protein, residues 1-112 share homology with the Ig variable (IgV) domain and residues 113-210 shares homology with Ig constant (IgC) domain (Freeman et al., J. Immunol., Vol. 143, pp. 2714-2722, 1989). B7-2 was also found to have similar structural features in the extracellular region. Similarly, CD28 and CTLA4 each have one IgV-like domain in the extracellular region.
Prior investigators have disclosed sequences encoding: human B7-1 domains are encoded by distinct exons in their respective genes as described for human B7-1 (Freeman et al., J. Immunol., vol. 143, pp. 2714-2722, 1989); human B7 (Azuma et al., Nature, vol. 366, pp. 76-79, 1993; or Selvakumar et al., Immunogenetics., vol. 36, pp. 175-181, 1992); rhesus monkey B7-1 (Villinger et al., J. Immunol., vol. 155, pp. 3946-3954, 1995); cat B7-1 (Hash et al., Thesis, Veterinary Pathobiology, Texas A & M, 1996); rabbit B7-1 (Isono et al., Immunogenetics., vol. 42, pp. 217-220, 1995); rat B7-1 (Judge et al., Intl. Immunol., vol. 7, pp. 171-178, 1995; Jackerott et al., Genbank Accession No. U10925, 1994); mouse B7-1 (Borriello et al., J. Immunol., vol. 153, pp. 5038-5048, 1994); human B7-2 (Freeman et al., Science, vol. 262, pp. 909-911, 1993); mouse B7-2 (Freeman et al., J. Expt. Med., vol. 178, pp. 2185-2192, 1993; or) and rat B7 genes (Judge et al., Intl. Immunol., vol. 7, pp. 171-178, 1995; Goodman, Genbank Accession No. U31330, 1995).
Prior investigators have also disclosed sequences encoding: mouse CTLA4 (Brunet et al., Nature, vol. 328, pp. 267-270, 1987); human CTLA4 (Dariavach et al., Eur J Immunol, vol 18, pp. 1901-1905, 1988); rabbit CTLA4 (Isono and Seto, Immunogenetics, vol. 42, pp. 217-220, 1995); rat CTLA4 (Oaks et al., Immunogenetics, vol. 43, pp. 173-174, 1996); and bovine CTLA4 (Parsons et al. Immunogenetics, vol. 43, pp. 388-391, 1996).
Messenger RNA of different sizes have been identified for B7-2 genes by Northern blot hybridization (Inobe et al., Biochem. Biophys. Res. Communic., vol. 200, pp. 443-449, 1994; or Boriello et al., J. Immunol., vol. 155, pp. 5490-5497, 1995). These B7-2 mRNA species have been assumed to be generated through alternative splicing or differential use of polyadenylation sites.
There remains a need for compounds and methods to regulate an immune response by manipulation of the function of B7-1 and/or B7-2.